Modulation of hypoglossal motoneuron excitability by NK1 receptor activation in neonatal mice in vitro

1. The effects of substance P (SP), acting at NK1 receptors, on the excitab ility and inspiratory activity of hypoglossal (XII) motoneurons (MNs) were investigated using rhythmically active medullary-slice preparations from ne onatal mice (postnatal day 0-3). 2. Local application of the NK1 agonist [SAR(9),Met (O-2)(11)]-SP (SPNK1) p roduced a dose-dependent, spantide- (a non-specific NK receptor antagonist) and GR82334-(an NK1 antagonist) sensitive increase in inspiratory burst am plitude recorded from XII nerves. 3. Under current clamp, SPNK1 significantly depolarized XII MNs, potentiate d repetitive firing responses to injected currents and produced a leftward shift in the firing frequency-current relationships without affecting slope . 4. Under voltage clamp, SPNK1 evoked an inward current and increased input resistance, but had no effect on inspiratory synaptic currents. SPNK1 curre nts persisted in the presence of TTX, were GR82334 sensitive, were reduced with hyperpolarization and reversed near the expected E-K. 5. Effects of the alpha (1)-noradrenergic receptor agonist phenylephrine (P E) on repetitive firing behaviour were virtually identical to those of SPNK 1. Moreover, SPNK1 currents were completely occluded by PE, suggesting that common intracellular pathways mediate the actions of NK1 and alpha (1)-nor adrenergic receptors. In spite of the similar actions of SPN,, and PE on XI I MN responses to somally injected current, alpha (1)-noradrenergic recepto r activation potentiated inspiratory synaptic currents and was more than tw ice as effective in potentiating XII nerve inspiratory burst amplitude. 6. GR82334 reduced XII nerve inspiratory burst amplitude and generated a sm all outward current in XII MNs. These observations, together with the first immunohistochemical evidence in the newborn for SP immunopositive terminal s in the vicinity of SPNK1-sensitive inspiratory XII MNs, support the endog enous modulation of XII MN excitability by SP. 7. In contrast to phrenic MNs (Ptak et al. 2000), blocking NMDA receptors w ith AP5 had no effect on the modulation of XII nerve activity by SPNK1. 8. In conclusion, SPNK1 modulates XII motoneuron responses to inspiratory d rive primarily through inhibition of a resting, postsynaptic, K+ leak condu ctance. The results establish the functional significance of SP in controll ing upper airway tone during early postnatal life and indicate differential modulation of motoneurons controlling airway and pump muscles by SP.